Central nervous system control of cough: pharmacological implications

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For many years the idea of a cough center in the brain dominated discussions in the field without any substantial progress in defining what this cough center is or how it functions. Substantial progress has now been made and many of the central neural elements involved in coughing are being described. Furthermore, hypothesis driven research into the function of these neural elements is providing exciting new leads for possible therapeutic targets. The concept of a specific, centrally acting drug for cough suppression is fast becoming a reality. This review summarizes the key findings from the past few years and provides a perspective on future directions for the development of novel antitussives.

Highlights

► Cough is a reflex or behavioral event accompanied by a preceding urge-to-cough. ► Brainstem and higher brain processing are involved in both cough and urge-to-cough. ► Brainstem targets for cough suppression include NMDA and opioid receptors. ► Higher brain targets for cough suppression are at present speculative.

Introduction

Any discussion of the central pharmacology of cough must also include a brief overview of the central nervous anatomical substrates that regulate coughing. Until relatively recently, few studies had tackled the topic of central control of cough, leading to an overuse of the simplistic concept of a ‘cough center’ to describe the seemingly black box of central nervous system (CNS) cough control. This lack of understanding of the CNS cough circuitry persisted despite significant advances in closely related disciples such as cardiovascular and respiratory control, and probably reflected in part a long standing controversy surrounding the identity of the afferent nerves that evoke coughing and also the difficulty of studying cough in animal preparations. However, recent advances using animal models and humans, in conjunction with seminal discoveries in the sensory pathways that evoke coughing, have rapidly increased our understanding of the CNS cough circuitry and its neurochemistry. The contents of the black box are being identified, and new ideas for cough suppression are arising from these discoveries. The discussion that follows reviews some of the most recent advances in this field of research and provides where appropriate the authors’ subjective commentary on the significance of these findings and possible future directions. Readers are directed to more extensive reports of data that are not considered recent.

Section snippets

Afferent input and brainstem processing

The available evidence suggests that reflexive cough is precipitated predominately, if not exclusively, by the activation of vagal afferent nerves that innervate the larynx, trachea and airways. Studies conducted in laboratory animals, and anecdotal evidence in humans, indicate that at least two different vagal afferent pathways can precipitate coughing. These pathways are differentiated by their relative sensitivities to mechanical and chemical stimuli and are reviewed in detail elsewhere

Central pharmacology of cough

Therapeutic preparations containing either codeine or dextromethorphan are currently the most effective and widely used treatment for unwanted coughing. The available evidence now seems to indicate that these compounds produce antitussive effects via a central site of action, although some debate remains as to where in the CNS codeine and dextromethorphan act (reviewed in [12, 13]). It is, however, widely agreed that better antitussives, with proven efficacy and lower side-effect profiles, are

Future directions

Cough is a highly complex neural event that can be evoked either reflexively (by multiple airway sensory pathways) or voluntarily (via descending cortical circuits). Overlaid onto this cough neural circuitry are regulatory inputs that can modify (suppress or enhance) the activity of the cough neural elements. Although the need for new drugs to treat chronic cough is widely accepted, the current state of play seems to focus on disrupting brainstem components of the cough pathway. Suppressing

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

SBM holds a current NHMRC of Australia Fellowship grant (454776) and MJF is a C.R. Roper Fellow, University of Melbourne. SBM and MJF are funded by an NHMRC of Australia project grant (566734).

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